Stabilized aromatic compounds and methods of obtaining the same



' UNITED sra'rss PATENT OFFICE v STABILIZED AROMATIC COLIPOUNDS ANDMETHOD OF OBTAINING THE SAME Edward W; Tiilitson, Grosse Pointe, Mich,as-

signor to Parke, Davis & Company, Detroit, Mich., agcorporationofMichigan No'Drawing. Application June 4, 1945,

Serial No. 597.599

The invention relatesto stabilize on of cyclic Examples oi. compoundswhich are stabili aromatic compounds containing oneormorerin a by theabouem'en cned compounds of formula carbon atoms to which areattached;subs v of the class hydroxy and amino rou ing substituted amino groups;

' More particularly, the inventi compositions containing aminoansubstituted carbocyclic aryl compounds s abilized against discolorationor oxidation, orother unde sired chemical and physical deterioration oralteration, by means of relatively small amounts ofiminoaminomethanesulflnic acid compounds of the general formula,

r a gpfl, xylenols Trimethyl phenols o. m, and p-Phenyl phenols n'mz lHalogenated phenols I I a-flydroxy-p-methylethylamino-Si-hydroxy ben-'zene or their tautomeric forms. represented by the nd p-Alkoxy-phenolsformula, v o, m, and p-Phenoxy phenols Halogenated phenoxy phenols i jBenzyl phenol v. 3-chloro-4-hexyl phenol mu 0 G-chIoro-o-xenol where Ris a member of the classhydroz'en' m mafia-1 :32: diphenyl lower alkylradicals. a use pma hthds The cyclic aromatic compounds; and and 5Naphth1su1gmc acids sitions containing the same, which I have foundv flcto be stabilized by the above mentioned imino- Guam!aminomethanesulflnic acid compounds are -Tert bhtyl'catechol thosecarbocyclic compoundshaving an aromatic mend nucleus such asthe'benzene, naphthalene, an- Isoeusenol thracene, phenanthrene, andlike nuclei. ortho eugenoi Hydroxy and/oramino' groups are attached toUrushiol the ring nuclear carbonatoms of the compounds I Morphine to bestabilized. Such amino'orfhydroxy com- 5 Apomorpmne pounds mayadditionally carry non-oxidizing Morph)! groups directly or indirectlysubstituted into their Methyl catechol nuclei which do not interfere hthe stabiliz- Epinephrine (methyl amino ethanol catechol) ing action ofthe iminoaminomethanesulflnic xeto fl methylamino-m p dihydrox ethylacidcompounds a l s such additional. 40 benzene and its salts with acidreacting subnon-oxidizing substituting r ups are. for exstances I ample,halogens (Hal), hydrocarbon radicals misopropyl catechol (R--) such asalkyl, aralkyl, aryl, alkaryl, cyph l catechol cloalbl, and-the like,ether radicals (-OR, flenzyl catechol where R is a hydrocarbon rad l sch a already ,p-Dihydroxy naphthalene mentioned); ketone yge r Leucoallzarin (0H), sulfhydryl (-810, amino group Alizarin,

(-NHs), substituted amino groups (-1133 and 0 011 -NRR). (where the Rgroups are as already de- 11 fined and may be the same ordifl'erenthydroso on carbon radicals), acylamino (NH acyl), sulfonicacid groups, (SOaX, where X is hydrogen or'a salt-forming group orradical) and carboxylic acid radicals (-COOX, where x l8 7-: drosen,alkyl or a salt-forming group or radical). o5 Aliurla -Propyl resorcinolButyl resorcinol Isobutyl resorcinol Amyl resorcinol Hexyl resorcinol2-ethyl hexyl resorcinol Diisobutyl resorcinol Capryl 3-chloro-4-hexylresorcinol 2,4-dialkyl resorcinols, e. g. di-secondary heml resorcinol,

' on CH: CHr-CHz-CHr-CHg-- Hydroquinone:

Methyl hydroquinone Ethyl hydroquinone Trimethyl hydroquinone Leucoquinizarin:

1,4-dihydroxy naphthalene 2-methvl-lA-dihydroxy napthalene4,4'-dihydroxy diphenyl ether Dibenzohydroquinone idihydroanthraquinone)Dihydrophthiocol Pyrogallol Pyrogallol dimethyl ether HydroKyhydroquinone Phloroglucinol Gallic acid Gallic acid methyl ester Gallicacid ethyl ester Eyrogallol carboxylic acid Polygallic acids Deuceflavorpurp Leuco nurpurin ll ydroaurine Aniline N-methyl aniline N-ethyianiline N-ethyl-toluldines Diphenyl amine p-Amino benzoic acid and itsalkylaminoalkyl esters such as novocain 4-amino-1-naphthoic acid and itsalkylaminoalkyl esters such as the p-diethylaminoethyl esterN-acetyl-o-phenylene diamine m-Phenylene diamine m-Toluene diaminep-Phenylene diamine Benzidine o. m, and p-Amino phenols o. m, andp-N-alkyl phenols- Alkyl-amino phenols Alkyl-amino rphenolsAikylaminoalkylamino phenols 1,4-amino-naphthol2-methyl-4-amino-naphthol-i 2-methyl-4-hydroxy-naphthylamine-1 o, m, andp-Amino thiophenol N-acyl-o. m. and p-amino thiophenol The above list ofcompounds illustrates the variety of substances which are stabilizedagainst deterioration by use of the iminoaminomethaner sulfinic acidcompounds of the present invention. However, the amino compounds canalso be stabilized in the form of their salts of nonoxidizing mineral ororganic acids, as well as in the form of their free base compounds.Examples of salts of the above listed amino compounds which can bestabilized and which are salts of non-oxidizing mineral or organic acidsare the sulfates, phosphates, sulfamates, hydro- 0 ammonium chloridemonohydr ate.

chlorides, hydrobromides, succinates, acetates, tartrates, citrates andlike salts.

I have found that very small quantities of the stabilizer are necessaryto obtain the desired effect, but exact quantities will vary with thedifferent compounds to be stabilized. Quantities useful in solutionsrange from a small fraction of one per cent up'to two or three per cent.I have found that when using aqueous solutions it is seldom necessary touse more than about 1% concentration of stabilizer. Theiminoaminomethanesulfinic compounds of the invention are inexpensive andexercise their specific stabilizing action on the hydrcxy, amino andhydroxyamino compounds of the invention in the presence of the pure, dryor liquid. states 01 the latter, as well as in solutions of the same inorganic or aqueous solvents and in mixtures which, in addition to thecompound to be stabilized, also contain other organic or inorganicsubstances of non-oxidizing nature. In general, the presence of areducing substance in mixtures which contain a hydroxy and/or amino compound to be stabilized has no effect upon the stabilizing effect of theiminoaminomethanesulfinate compounds of the invention.

The invention is illustrated by the following examples.

EXAMPLE I s 25 ml. of water is added. 0.02 g. ofp-tert.-octylphenoxyethoxyethyldlmethylbenzyl a In man i u no. chloridemonohydrate and suflicient sodium chloride (about 0.5 g.) to render thesolution isotonic at a volume of 100 ml. are added, the so lutiondiluted to 100 ml. with distilled water and sterilized by filtrationthrough a Mandler filter. The resulting water white solution has a pH ofabout 3 and is germicidal due to the added ptertoctylphenoxyethoxyethyldimethylbenzyl- This solution of epinephrinehydrochloride is unchanged in color and activity after standing forseveral years while a control sample prepared in exactly the same mannerbut substituting 0.1 B. 0! sodium bisulfite for theiminoaminomethanesulfinic cid is dark brown in color and has only 75% ofthe original epinephrine activity at the end of this time.

1 EXAMPLE l1 1 g. of epinephine is dissolved in 5 ml. of 4.2%hydrochloric acid and added to a solution of 1.0 g. ofiminoaminomethanesulflnic acid in 33 ml. of distilled water. Suflicientsodium chloride (about 0.5' g.) to render the solution isotonic at avolume oi ml. is added, the solution diluted to 100 ml. with distilledwater and sterilized by filtration through a Mandler filter. The re-,sulting colorless solution is unchanged in color and epinephrineactivity after aging for several .of water.

conditions.

the iminoam'inomethanesulfinic acid is brown in color and loses aconsiderable percentage of the epinephrine activity. I

VEXAHPLI m 0.11 3.01 epinephrine is dissolved in 0.7 ml. of 4.2%hydrochloric acid. the solution diluted to ml. and added to a solutionof 0.1 g. of iminoamlnemethanesulfinic acid dissolved in 25 ml. ofdistilled water. ml. with distilled water and sufilcient sodiu'mchlorideiabout 0.80 g.). to make the solution isotonic is added. Thissolution of epinephrine is colorless and retains all of its originalepinephrine activity after standing for several years. A control samplein which sodium bisulflte is substituted for iminoaminosulflnic acidremains colorless under these conditions but loses 20% of itsepinephrine activity.

Exsurm IV as a stabilizer instead of imlnoaminomethanesulflnic acidrapidly loses its epinephrine activity.

' Exmrns V l g. of the fl-diethylamin oethyl ester of 4-amino-l-naphthoic acid is dissolved in a minimal amount of 2%hydrochloric acid and the resulting solution added to a solution of 0.1gof n-butylaminoiminomethanesulfinic acid in 50 ml. About 0.5 g. ofsodium chloride is added, the solution diluted to 100 ml. with distilledwater and sterilized by filtration through a Mandler filter. Thiscolorless solution does not darken on aging jor several years or loseany appreciable amount of its local anesthetic ac- The solution isdiluted to100 Exsurtn VIII 0.75 g. or iminoaminomethanesulflnic acid isdissolved in 9 ml. of 95% ethanol and the. resulting solution added to80 ml. of a saponified cresylic acid solution having a phenolcoeflicient of about 6.6. The resulting solution when diluted isvaluable for use as a surgical and general disinfectant. Theconcentrated solution 'does not darken on exposure to air whereas acontrol sample prepared in the same manner butcon taining noiminoaminomethanesulflnic acid rapidly turns a dark brown color whenexposed to the air.

EXAIIPLI 11:

0.2 g. of boric acid is dissolved in 30 ml. of glycerine by heating. Thesolution is cooled and added to a paste consisting of 0.23 g. of gumtragacanth, 0.53 g. of sodium alginate and 17 ml.- of glycerine and theresulting mixture is stirred until a smooth paste is obtained. 300' ml.or water is added, the mixture heated to 185 F. for 20 minutes and thencooled. 0.34 g. of 2,4-disec-hexylresorcinol and 0.2 g. ofiminoaminomethanesulfinic acid are added with stirring.

. The resulting mixture is suitable for a surgical lubricant and inspite of the fact that it contains 2,4-di-sec-hexylresorcinol, a veryunstable compound, the preparation remains free from color over a periodoi. several years.

I have also found that black spent wheat germ oil may be recovered bytreatment of the crude oil with a small amount of ammonia andimmoaminomethanesulflnic acid to obtain alight yellow stable oil.

The imlnoaminomethanesulflnic acid compounds of the present inventionare prepared by the oxidation of the corresponding thioureas withhydrogen peroxide. Iminoaminomethanesulfinic acid, NH2C=NHSO:H, isprepared as described in U. S. Patent No. 2,150,921 while .the

tivity, while a control sample prepared without a stabilizer becomesdark and rapidly loses its local anesthetic activity under the sameadded, the solution diluted to 100 m1. and sterl j lized by filtrationthrough a Mandler filter. This;

colorless solution retains all of its local anesthetic properties and iscolorless evenafter standing exposed to the air for several years.chloromethyl-2-propanol is added to this preparation solely for itsermicidal properties.

EXAMPLE VII 0.1 g.' of n-propylaminoiminomethanesulfinic acid isdissolved in 25 ml. of distilled water and added to a solution of 0.1 g.of B- diethylaminoethyl p-aminobenzoate and 0.8 g. of sodium chloridedissolvedin 3.3 ml. of 4% hydrochloric acid and the resulting solutiondiluted to 100 ml.

The 2-tri- N-substituted iminoaminomethanesulfinic acids are prepared inan analogous manner to those described in detail in the followingspecific examples: Y

Exams X Preparation of n-promlaminoiminomethanesulfinic acid 44 g. ofn-propylthiourea is dissolved in 200 ml. of dioxane and 5 ml. of water.The mixture is cooled to about 0 C. By the addition of solid carbondioxide and 25.4 g. (87.5 cc. of a 29% solution) of hydrogen peroxideadded dropwise, with stirring keeping the temperature below 10 C Thereaction mixture is stirred at 10 C. for about two hours after all thehydrogen peroxide is added and then concentrated in vacuo. The yellowneedles of the n-propylaminoiminosulflnic acid which separate areremoved by filtration and washed with a small amount of absolutealcohol; M. P. -1l2 C. with efiervescence to give a milky liquid.

A sample of this compound when dissolved in color.

EXAMPLE m Preparation of n-butylaminoiminomethanesulflnic acid 50 g. ofn-butylthiourea is dissolved in a mixture of 20 ml. of water and 100 ml.of dioxane by warming. The solution is cooled to C. and maintained belowC. while 89 cc. of 29%. hydrogen peroxide solution is added dropwisewith stirring. Stirring is continued for about two hours after all thehydrogen peroxide has been added and then the solid product removed byfiltration. The crude n-butylaminoiminomethanesulfinic acid isrecrystallized from water; M. P. 126 C. with efifervescence. To preventdecomposition of the product during recrystalization, it is advisable touse sufiicient water to efiect solution of the material at about 50 C.

The iminoaminomethanesulfinic acid compounds which I use as stabilizersare non-toxic and are well tolerated when administered to animals orhumans by the subcutaneous, intravenous or intramuscular routes as wellas by the oral route. More particularly, these iminoaminomethanesulfinicacid compounds are at least as new toxic as sodium bisulfite. Forexample, the oral toxicity data of iminoaminomethanesulflnic acid inmice are; M. T. D. (maximum tolerated dose) 600 mg./,kg. and M. L. D.(minimum lethal dose) 750 mg./kg., while the corresponding toxicity datafor sodium bisuffite are: M. T. D. 750 mg./kg. and M. L. D. 900 mgJkg.

I have found that the iminoaminomethanesulfinic acid compounds which Iuse are at least twice as effective as sodium bisulfite when used toprevent deterioration or alteration of the various unstable productsmentioned herein.

I claim:

1. A stabilized aromatic carbocyclic compound containing a nuclearsubstituent of the class consisting of hydroxyl and amino groups andacid addition salt groups corresponding to said amino groups, saidcarbocyclic compound having incorporated therewith at least a smalltraction of 1% of an iminoaminomethanesulflnic acid of the formula,

to stabilize said carbocyclic compound against deterioration, R of theformula being a. member of the class consisting of hydrogen and loweralkyl radicals.

2. A stabilized aromatic carbocyclic compound containing a nuclearsubstituent of the class consisting of hydroxyl and amino groups andacid addition salt groups corresponding to said amino groups, saidcarbocyclic compound having incorporated therewith at least a smallfraction of 1% of iminoaminomethanesulflnic .acid of the formula,

to stabilize said carbocyclic compound against deterioration.

3. A stabilized aromatic carbocyclic compound containing a nuclearhydroxyl group, said carbocyclic compound having incorporated therewithat least a small fraction of 1% of an iminoaminomethanesulflnic acid 01the formula,

NH R'NH-BO=H to stabilize said carbocyclic compound againstdeterioration, R of the formula being a member of the class consistingof hydrogen and lower alkyl radicals.

4. A stabalized benzene compound containing a nuclear substituent of theclass consisting oi hydroxyl and. amino groups and acid addition saltgroups corresponding to said amino groups, said phenolic compound havingincorporated therewith at least a small fraction of 1% of animinoaminomethanesulflnic acid of the formula,

to stabilize said phenolic compound against deterioration, R. of theformula being a member of the class consisting of hydrogen and lowerallryl radicals.

5. A stabilized phenol having incorporated therewith at least a smallfraction oi 1% of iminoaminomethanesulfinic acid to stabilize saidphenol against deterioration.

6. A. stabilized phenol having incorporated therewith at least a smallfraction of 1% of n-propylaminoiminomethanesulfinic acid of formula,

to stabilize said phenol against deterioration.

7. A stabilized phenol having incorporated therewith at least a smallfraction of 1% of 11-bittylaminoiminomethanesulflnic acid of formula,

to stabilize said phenol against deterioration.

8. A stabilized aqueous solution of an aromatic carbocyclic compoundcontaining a nuclear substituent of the class consisting of hydroxyl andamino groups and acid addition salt groups corresponding to said aminogroups, said carbocyclic compound having incorporated therewith at leasta small fraction of 1% of an iminoaminomethanesulfinic acid of theformula,

to stabilizesaid carbocyclic compound against deterioration, R of theformula being a. member of the class consisting of hydrogen and loweralkyl radicals.

9. A stabilized aqueous solution of an aromatic carbocyclic compoundcontaining a nuclear substituent'oi the class consisting of hydroxyl andamino groups and acid addition salt groups corresponding to said aminogroups, said carbocyclic compound having incorporated therewith at leasta small fraction'of 1 of an iminoaminomethanesulfinic acid of theformula,

to stabilize said carbocyclic compound against deterioration.

10. A stabilizer aqueous solution of stabilized aromatic carbocycliccompound containing a nu- 9 clear hydroxyl group, said carbocycliccompound having incorporated therewith at least a small fraction of 1%of an iminoaminomethanesulfinic acid of the formula,

NH R'NHH!SO:H

to stabilize said carbocyclic compound against to stabilize saidcarbocyclic compound against deterioration, R of the formula being amember of the class consisting of hydrogen and lower alkyl radicals.

12. A stabilized aqueous solution of a phenol having incorporatedtherewith at least a small fraction of 1% of iminoaminomethanesulfinicacid to stabilize said phenol against deterioration.

13. A stabilized aqueous solution of a phenol having incorporatedtherewith at least a small fraction of 1% ofn-propylaminoiminomethanesulflnic acid of the formula,

NH cmcmcmNn-r'-som to stabilize said phenol against deterioration.

14. A stabilized aqueous solution of a phenol having incorporatedtherewith at least a small fraction of 1% ofn-butylaminoiminomethanesulfinic acid of formula,

tostabilize said phenol against deterioration.

15. The method of stabilizing an aromatic carbocyclic compound andcompositions containing the same against deterioration, said compoundcontaining a nuclear substituent of the class consisting of hydroxyl andamino groups and acid addition salt groups corresponding to said aminogroups, which comprises incorporating therewith at least a smallfraction of 1% of r m RN'H-CSO2H R of the formula being a member of theclass consisting of hydrogen and lower alkyl radicals. 16. The method ofstabilizing an aromatic carbocyclic compound and compositions containingthe same against deterioration, said compound containing a nuclearsubstituent of the class consisting of hydroxyl and amino groups andacid addition salt groups corresponding to said amino groups, whichcomprises incorporating therewith at least a small fraction of 1% ofiminoaminomethanesulfinic acid of the formula,

lFIH na e-soul 17. The method of stabilizing an aqueous solution of aphenol against deterioration which comprises incorporating therewith atleast a small fraction of 1% of iminoaminomethanesulfinic acid of theformula,

l\'l[ II2N-(I.LI-SORH 18. The method of stabilizing an aqueous solutionof a phenol against deterioration which comprises incorporatingtherewith at least a small fraction of 1% of n-propylaminoiminomethanesulfinic acid of the formula,

NH omcmommr-tt-som 19. The method of stabilizing an aqueous solution ofa phenol against deterioration which comprises incorporating therewithat least a small fraction of 1% of n-butylaminoiminomethanesulfinic acidof the formula,

511 cmomcmcumu jsmu EDWARD W. TILLITSON.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,047,144 Kharasch July 7, 19362,130,322 Kharasch Sept. 13, 1938 2,347,446 Walker Apr. 25, 1944

